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- Title
Nfkb1 is a haploinsufficient DNA damage-specific tumor suppressor.
- Authors
Voce, D J; Schmitt, A M; Uppal, A; McNerney, M E; Bernal, G M; Cahill, K E; Wahlstrom, J S; Nassiri, A; Yu, X; Crawley, C D; White, K P; Onel, K; Weichselbaum, R R; Yamini, B
- Abstract
NF-κB proteins play a central and subunit-specific role in the response to DNA damage. Previous work identified p50/NF-κB1 as being necessary for cytotoxicity in response to DNA alkylation damage. Given the importance of damage-induced cell death for the maintenance of genomic stability, we examined whether Nfkb1 acts as a tumor suppressor in the setting of alkylation damage. Hprt mutation analysis demonstrates that Nfkb1−/− cells accumulate more alkylator-induced, but not ionizing radiation (IR)-induced, mutations than similarly treated wild-type cells. Subsequent in vivo tumor induction studies reveal that following alkylator treatment, but not IR, Nfkb1−/− mice develop more lymphomas than similarly treated Nfkb1+/+ animals. Heterozygous mice develop lymphomas at an intermediate rate and retain functional p50 in their tumors, indicating that Nfkb1 acts in a haploinsufficient manner. Analysis of human cancers, including therapy-related myeloid neoplasms, demonstrates that NFKB1 mRNA expression is downregulated compared with control samples in multiple hematological malignancies. These data indicate that Nfkb1 is a haploinsufficient, pathway-specific tumor suppressor that prevents the development of hematologic malignancy in the setting of alkylation damage.
- Subjects
NF-kappa B; DNA damage; TUMOR suppressor genes; CELL-mediated cytotoxicity; GENETIC mutation; LYMPHOMAS; CANCER treatment
- Publication
Oncogene, 2015, Vol 34, Issue 21, p2807
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2014.211